Postmenopausal women have a higher incidence of diseases such as metabolic syndrome, cardiovascular and renal disease than premenopausal women. To begin to uncover genes and pathways that contribute to these adverse effects of aging in the postmenopausal woman, we propose two distinct strategies for discovering novel genes and pathways that may contribute to the increased risk postmenopausal women face towards these diseases. We will take advantage of the "four core genotypes" mouse model in which sex chromosome effects can be separated from the gonadal sex thus enabling comparisons among XX and XY animals independently of whether they were born with ovaries (e.g., XX- vs. XY-females) or testes (XX- vs. XY-males). While recent microarray studies in mice have demonstrated that thousands of genes are regulated by gonadal hormones, the number of genes regulated by the sex chromosome complement independently of the gonadal hormones is far more limited. Thus, we expect to discover a handful of genes (<10) that are differentially regulated by the sex chromosome complement (SCC) in the ovarian hormone deficient female during over activity of the renin angiotensin system (RAS). Aim 1 will use a tightly focused microarray approach leveraging our ability to differentiate SCE from gonadal sex to identify genes in the kidney that are differentially regulated by the SCC in the Ang II infused E2-deficient female. Aim 2 will use a candidate gene approach to test the hypothesis that the regulation of the tissue-specific renin angiotensin system (RAS) in the kidney by ovariectomy and hypertension is sex chromosome dependent. We hypothesize that the interaction between the XX SCC with the E2-deficient state of ovariectomy tips the vasoconstrictor/vasodilator balance of the renal RAS towards vasoconstriction to a greater extent than in the XY-Female by increasing plasma and renal levels of Ang II, the ratio of the Ang II synthetic enzyme, angiotensin converting enzyme (ACE) to the catabolic enzyme, angiotensin converting enzyme 2 (ACE2) and the ratio of the type 1 angiotensin receptor (AT1R) to the vasodilator type 2 angiotensin receptor (AT2R). PUBLIC HEALTH RELEVANCE: This project is designed to make new discoveries into why postmenopausal women are at increased risk for diseases like metabolic syndrome, hypertension and cardiovascular disease compared to premenopausal women. We will make these new discoveries by studying sex chromosome effects independently of the ovarian hormones using a unique animal model in which we can separate, for the first time, sex chromosome differences between males (XY) and females (XX) from the sex hormone differences (e.g., differences in estrogen and testosterone levels). By discovering new genes and pathways responsible for the increased incidence of these diseases in ovarian deficient females, new therapeutic treatments are likely to ensue for post-menopausal women and women with ovarian hormone deficiency.